Project 3 will test with PET neuroreceptor imaging techniques one of the central theme of this center, i.e. that alterations in serotonin (5-HT) transmission in key brain regions confers vulnerability to suicidal attempts. Postmortem studies from our group suggest that decreased 5-HT transporters (SERT) and increased 5-HT1A receptor densities in the amygdala and the ventro-lateral portion of the orbitofrontal cortex might be associated with a vulnerability to suicide. The results are consistent with the role of the amygdala and the orbitofrontal cortex in the modulation of aggressivity and impulsivity, respectively. These hypotheses will be tested over five years by studying in vivo the distribution of SERT with [11C]McN 5652 and 5-HT/1A receptors with [11C]WAY 100635 in three groups of subjects. Group 1 will include patients with major depression and a history of a severe suicide attempt. Group 2 will include subjects with major depression, but without any history of suicide attempts. Group 3 will include healthy controls. Each group will include 30 subjects studied over 5 years. Groups will be matched on age, gender, race, socioeconomic background and nicotine smoking. In addition, groups 1 and 2 will be matched for severity of depression (both in terms of the current episode, and in terms of previous history of depression). Alterations associated with vulnerability to major depression are expected to be found in both groups 1 and 2, while alterations associated with suicide vulnerability are expected to be found only in group 1. Thus, this design will test one of the central hypotheses of this Center, i.e. that alterations of 5-HT function confer a vulnerability to suicide attempts per se, over and above alterations of 5-HT function that underlie vulnerability to suicide attempts per se, over and above alterations of 5-HT function that underlie vulnerability to major depression. A similar hypotheses will also be tested in a group of schizophrenic subjects studied in project 4C. Thus, patients with schizophrenia with and without a history of suicidal attempts will be compared, to test if neurochemical abnormalities associated with vulnerability to suicide detected in this study (depressed subjects) are also present in another diagnosis group associated with high suicidal risk.